Method of making 13-cis prostaglandin derivatives

ABSTRACT

13-Cis prostaglandin derivatives; cis-octenol ether copper (I) lithium reagents and methods of making such reagents and using the reagents to prepare the 13-cis prostaglandin derivatives. The 13-cis prostaglandin derivatives exhibit prostaglandin-like pharmacological properties and are further useful as intermediates for the corresponding prostaglandin isomers having the normal 13-trans configuration.

United States Patent Kluge et al.

[451 Feb. 18,1975

METHOD OF MAKING l3-CIS PROSTAGLANDIN DERIVATIVES Inventors: Arthur F.Kluge, Palo Alto; Karl G.

Untch, Los Altos; John H. Fried, Palo Alto, all of Calif.

Assignee: Syntex, Inc., Palo Alto, Calif.

Filed: July 18, 1972 Appl. No: 272,880

US. Cl 260/240 R, 260/345.7, 260/345.8, 260/347.3, 260/347.4, 260/410.9R,

260/413, 260/438.1, 260/456 R, 260/468 D, 260/514 D, 424/30 S, 424/317Int. Cl. C07c 61/36, C07c 61/32 Field of Search..... 260/468 D, 514 D,514 CA, 260/345.7, 345.8, 410.9 R, 413, 240 R References Cited OTHERPUBLICATIONS Kluge et al., JACS 94, 9256 (1972).

Primary ExaminerR0bert Gerstl Attorney, Agent, or FirmGerard A.Blaufarb; Lawrence S. Squires; William B. Walker [57] ABSTRACT 14Claims, N0 Drawings METHOD OF MAKING l3-CIS PROSTAGLANDIN DERIVATIVESBACKGROUND OF THE INVENTION 1. The Invention This invention relates tomethods of preparing prostaglandis and prostaglandin derivatives. In afurther aspect, this invention relates to l3-cis prostaglandinderivatives and methods of making such derivatives. In a still furtheraspect, this invention relates to cis-octenol ether copper"lithiumreagents and methods of preparing such reagents. In anotherfurther aspect, this invention relates to racemic octenol ether copper"lithium reagents and also optically active (R)- or (S)-octenol ethercopper" lithium reagents. In still another aspect, this inventionrelates to methods of preparing cis prostaglandin derivatives, usingsuch octenol ether copper lithium reagents. This invention also relatesto methods of preparing prostaglandins by the rearrangement of l3-eisprostaglandins to the corresponding l3-trans isomers.

2. The Prior Art Prostaglandins are a group of chemically related20-carbon chain hydroxy fatty acids having the basic skelton of prostanoicacids:

7 3 1 a 'WAZ/ coon The prostaglandins having a hydroxy grroup at the C-l1 position and a keto group at the C-9 position are known as the PGEseries, those having a hydroxy] group in place ofthe ,keto group areknown as the PGF series and are further designated by an a or [3 suffixto indicate the configuration of the hydroxyl group at said position.The natural compounds are the a-hydroxy substituted compounds. They maycontain different degrees of unsaturation in the molecule, particularlyat C-5, C-l 3 and C-l7, the unsaturation is also indicated by a suffix.Thus, for example, PGE refers to a prostanoic acid having a trans olefinbond at the 13- position. For a review on prostaglandins and thedefinition of primary prostaglandins, see, for example, S. Bergstrom,Recent Progress in Hormone Research 22, pp. 153-175 (I966) and Science157, page 382 (1967) by the same author.

Prostaglandins are widely distributed in mammalian tissues and have beenisolated from natural sources in very small amounts. In addition anumber ofthe natural occurring prostaglandins have been prepared bychemical synthesis; note, for example, .I. Am. Chem. Soc. 91, 5675(1969), J. Am. Chem. Soc. 92, 2586 (1970) and .I. Am. Chem. Soc. 93,1489-4493 (1971) and references cited therein, W. P. Scheider et al, J.Am. Chem. soc. 90. 5895 (1968), U. Axen et al, Chem. Commun., 303(I969), and W. P. Schneider, Chem. Commun. 304 (I969).

Because of the remarkable range of biological and pharmacologicalproperties exhibited by this family of compounds, a great deal ofinterest has focused upon such compounds and accordingly we havediscovered novel l3-cis prostaglandin derivatives and felicitous highyield processes and reagents for preparing such l3-cis prostaglandinderivatives and prostaglandins.

2 SUMMARY OF THE INVENTION In summary the l3-cis prostaglandin compoundof the invention can be represented by the following generic formula:

wherein n is a whole integer of from 2 through 8; R is hydrogen, alkylhavingfrom one through l0 carbon atoms, chloroethyl, dichloroethyl, ortrichloroethyl; R is hydrogen, hydroxy or' acid labile ether having fromthree through l0 carbon atoms; R is oxo or the group ()R is hydroxy oracid labile ether and wherein the wavy line at C-IS indicates either thea or B configuralines at the C-8, C ll and C-l2 indicate that therespective configurations can be a or [3 provided that the relativeconfigurations at C-8 and. C-1 2 and C-l l and C-l2 are both trans.

In summary the cis-octenol ether copper" lithium reagent, of theinvention, comprises a complexed (dl)- or optically active (R)- or(S)-cis-l-octen3-ol 3-ether copper" lithium in a suitable inert organicsolvent mixture.

In summary the process, of the invention. for preparing the octenolether copper lithium reagent comprises (l) preparing a first solution bythe admixture of a suitable alkyl lithium with a (dl)-, (R)- or(S)-l-iodo-cis-l-octen-3-ol 3-ether in a suitable inert organic solventunder controlled conditions; (2) preparing a copper" salt solution in asuitable inert organic solvent; (3) admixing a complexing agent witheither the first solution or with the copper salt solution depending onthe particular complexing agent and provided that a complexing agent isnot already inherently present in the copper salt solution; and (4)admixing the first solution with the copper salt solution undercontrolled conditions.

In summary, the process of our invention for preparing l3-cisprostaglandin derivatives comprises treating a2-(earboalkoxy-alkyl)-l-oxo-cyclopent-Z-ene, or 4- hydroxy ethersthereof, with the complexed octenol ether copper" lithium reagent in aninert organic solvent mixture, under reactive conditions, therebyobtaining the corresponding l3-cis-l l-desoxyprostaglandin IS-etherderivatives or the corresponding l l-ethers thereof.

In summary, the process of the invention for preparing prostaglandinscomprises preparation of the corresponding l3-cis prostaglandins,followed by rearrangement of the l3-cis olefin bond to a l3-trans olefinbond.

The invention will be further described herein below.

FURTHER DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS Thel3-cis prostaglandin compounds of the invention can be represented interms of normal and retro isomer configurations by the followingformulas:

tion or isomeric mixtures thereof and wherein the wavy (II) (IIr)mixtures of the a and B configurations.

The above formulas represent individual isomers and racemic anddiastereomeric mixtures and both the re- 1 (CH2) c0 11 spectiveindividual isomers and racemic and disasteromeric mixtures thereof areencompassed within the invention. 7

Also encompassed within the invention are pharmaceutically acceptablesalts of the above compounds wherein R is hydrogen.

The preferred R substituents are hydrogen and methyl. The preferred Rsubstituents are hydrogen and hydroxy. The preferred OR substituent ishydroxy. Also, preferably n is 6. The particularly preferred compoundscan be represented in terms of their preferred isomer and racemic pairsby the following formulas, wherein the horizontally oriented pairsrepresent mirror images:

1' x (CH CO R (CH 00 a (III) (IIIr) (CH CO R 2g (IVr) on 0H ll R1: i (CHCO R I I (CH CO W) (Vr) OH on 1' I 1' (CH CO R ,(CH CO R (VI) (VIr) OHor! E 1- 1- (VII) (CH2) 6C02R (CH2) 6CO2R (vnr) OH OH 1' 1 1' (CH2) c011 (CH2) 00 1:

(VIIIr) (CH CO R 2 6 2 1 I (CH2) 6CO2R HO OH (CH CO R 110' HO OH (XI) 7(XIr) (CH2) 6COZR OH OH "-oH QCIIr) .(CH) co R (cn co R 2 e 2 2 e 2 HOOH Ho H (XIII) (XIIIL) (ca co R HQ I OH (XIV) (XIVI) wherein R" ishydrogen methyl. The octenol ether copper" lithium reagent of theinlllustrations of typical l3-cis prostaglandins, of the vention is amixture consisting essentially of (d1) and/or invention, can be hadherein below by reference to the optically active (R) isomers and/oroptically active (S) Examples isomers of compounds having the formulas:

CH] Cu Li and [CH3 (CH gHCH CH]Cu LiX wherein the (c) over the doublebond indicates the cis configuration; X is a halide; OR is an acidlabile ether and the wavy line indicates either a (dl) mixture withrespect to this asymmetric center or the optically active (R) or (S)isomer; complexed by an electronrich neutral complexing reagent, whichcoordinates with transition metals, in a suitable inert solvent mixture.

Typically, and preferably, the compounds of the above formulas areeither a racemic (dl) mixture or the pure (R) or (S) optically activeisomer. The optically active (R) and (S) isomers are especiallypreferred as they yeild a selective B or a configuration at C-15 withrespect to the corresponding asymmetric center in the l3-cisprostaglandin product. Also where it is desired to use the octenol ethercopper" lithium reagent to produce a prostaglandin ether derivativehaving an easily cleavable l5-ether group, the preferred OR group is20'-methoxyprop-2'-oxy.

Suitable halides are fluoride, chloride, bromide, and iodide. Thepreferred halide is iodide. Suitable inert solvent mixtures include, forexample, mixtures of alkane and ether solvents. Suitable alkane solventsinclude, for example, pentane, hexane, heptane, and the like. Suitableether solvents include diethyl ether, methyl ethyl ether and the like.The preferred solvent mixture is a mixture of hexane and diethyl ether.Typically, a solvent concentration in the range of about from 0.5 to 50wt. percent, preferably 2 to percent, based on the octenol ethercomponent is used. However, the particular solvent concentration used islargely a matter of convenience and concentrations both above and belowthis range can also be used.

Suitable complexing reagents include, for example; (1)alkylalkylenediamines having the formula R,'R 'N-(CH -NR R wherein n isthe whole integer 2 or 3, and R R R and R are idependently selected fromthe group of alkyls having from one through four carbon atoms. Thus,suitable alkylalkylenediamines include, for example, N,N,N-tetramethylmethylenediamine and N,N,N',N'-tetramethylpropylenediamines,etc.; (2)naphthalene bridge diamines having the formula:

wherein R R R and R are as defined herein above; (3) alkylpiperazineshaving the formula:

I I R bl 2 wherein R, and R are as defined herein above; (4) polycyclicdiazoheterocyclics such as, for example, sparteine; and the like; (5)trialkyl (C through C phosphites such as, for example,trimethylphosphite, triethylphosphite; tri(N-propyl)phosphite;triisopropyl- 8 phosphite; tri(n-butyl)phosphite; triisobutylphosphite;and the like; trialkyl (C through C phosphines such as, for example,trimethylphosphine; tri(npropyl)phosphine; triisopropylphosphine;triisobutylphosphine; tri(n-butyl)phosphine; triethylphosphine; and thelike. Combination complexing reagent-copper salts such as, for example,bis-(trimethylphosphite) copper" iodide and the like.

The preferred complexing reagents are tetraalkylalkylenediamines, asdefined above, trialkylphosphites selected from the group consisting oftrimethylphosphite, triethylphosphite, tri(n-propyl)phosphite,triisopropylphosphite, tri(n-butyl)phosphite, and triisobutylphosphite;trialkylphosphines selected from the group consisting oftrimethylphosphine, triethylphosphine, tri(n-propyl)phosphine,triisopropylphosphine, tri(nbutyl)phosphine and triisobutylphosphine;and the combination complexing reagent and copper" halide salt,bis(trimethylphosphite) copper" iodide, The especially preferredcomplexing reagents are N,N,N,', N-tetramethylethylenediamine;trimethylphosphite; tri(n-butyl) phosphine and bis(trimethylphosphite)copper iodide.

Definitions As used herein above and below, the following terms have thefollowing meanings unless expressly stated to the contrary. The termalkyl includes both straight chain and branched chain alkyl groupshaving from one through 10 carbon atoms. The term lower alkyl refers toboth straight chain and branched chain alkyl groups having from onethrough six carbon atoms. The term lower alkoxy refers to the group OR"wherein R" is lower alkyl. The term cycloalkyl refers to cycloalkylgroups having from five through seven carbon atoms such as, for example,cyclopentyl, cyclohexyl and the like.

The term acid labile ether refers to those acid labile ether groupswhich can be cleaved by mild acid hydrolysis, and preferably having fromthree through 10 carbon atoms. Typical acid labile ether groups include,for example, l'-methoxyprop-2'-oxy; l-methoxyethoxy; l-ethoxyethoxy;phenoxymethoxy; 2-methoxyprop- 2-oxy; tetrahydropyranyl-2-oxy;tetrahydrofuran-2'- oxy; 2-butoxyprop-2'-oxy; l'-pent-l oxycyclohexyl-l-oxy; and'the like.

The terms acid and base labile acyloxy groups and acid and basehydrolyzable acyl groups refer to acid labile esters and acyl groups andbase labile ester and acyl groups conventionally employed in the art,preferably those derived from carboxylic acids of one to 12 carbonatoms. Typical hydrolyzable acyl groups thus include, acetyl, propionyl,butyryl, t-butyryl, valeryl, isovaleryl, hexanoyl, heptanoyl, octanoyl,nonanoyl, undecanoyl, lauroyl, benzoyl, p-methoxybenzoyl, pnitrobenzoyl,phenylacetyl, phenylpropionyl, 0-, m-, p-methylbenzoyl,B-cyclopentylpropionyl, dihydrocinnanyl, and the like.

The term complexing reagent refers to electron-rich neutral substances,commonly referred to as ligands, which are capable of coordination withtransition metals. Typical ligands include, for example, tertiaryamines, phosphines, phosphites, sulfides, cyanides, isonitriles and thelike.

The term halide refers to fluoride, chloride, bromide, and iodide.

The prostaglandin and prostaglandin derivatives have been describedherein above and below, as prostanoic acid derivatives. The termprostanoic acid refers to the structural configuration indicated hereinabove in the ture of the indicated st r ucture an d its mirror image:

wherein the dotted bond line indicates the a configuration and the solidbond line indicates the B configuration.

The term retro designates one isomer of an actual or hypothetical isomerpair wherein the side chain, attached to the C-8 and C-l2 positions ofprostanoic acid, have the opposite configuration to the precedingreference isomer (which has the C-8, C-l2 configuration of prostanoicacid), and with respect to retro compounds, the term epi indicates asubstituent configuration, the same as the preceding reference isomer atthat position. The cis or trans double bond orientation is the same inboth the reference isomer and its retro isomer. Thus, for example, 9 1,Ila, ISa-trihydroxy-prost-cis- 13-enoic acid has the structuralcdfinjgilrtifi;

COOH

The above structure could also be named as retro-9B, l 1,8,lSa-trihydroxy-prost-cis-i 3-enoic acid. 7

Also the designation l3-Cis-PGE or PGF refers to an isomer having thesame configuration as the prostaglandin isomer designated by conventionas PGE or PGF but having the cis configuration with respect to the13-olefin double bond instead of trans. Similarly, the termsretro-l3-cis-PGE, and retro-l3-cis-PGF refer to the corresponding isomerwherein the l3-olefin double bond is cis and the substituents at theremaining asymmetric centers have configurations opposite to that of theprostaglandin designated by convention as PGE, or PGF,. Also withrespect to the C-8, C-ll, C-l2, Cl 3 and C-l positions, the same numberdesignation will be used regardless of the actual number of carbon atomsin the upper (acid) chain. Accordingly, in describing a compound havinga smaller upper chain than prostanoic acid, the term o-desalkylene willbe used to indicate this difference thus, for example, the term6-desbutylene-9a, lla, lSa-trihydroxy-prost-cisl3-enoic acid refers tothe compound having the structure:

mirror ima e Similarly, the term 6-homoalkylene will be used to indicatean upper chain length longer than the normal protanoic acid upper chainlength. Thus, for example, the term 6-homoethylene-9a, 1 la,ISa-trihydroxyprost-cis-13-enoic acid refers to a compound having thestructure:

Considering now our process for preparing the octenol ether copperlithium reagent, in greater depth, it is essential that the process beconducted by preparing two distinct sub-component solutions, onecontaining the octenol ether lithium component and one containing thecopper" component and then admixing these solutions under controlledconditions. in addition, a particular one of the sub-component solutionsmust also contain the complexing reagent, depending on the particularcomplexing agent used.

Accordingly, considering the process in detail, the ocetenol ether andlithium sub-component solution can be prepared by admixing a suitablealkyl lithium with a suitable iodo octenol ether in a suitable solventat temperatures in the range of about from l00 to 20C for about from 1to 60 minutes. Preferably this treatment is conducted at temperatures inthe range of about from to 0C for about from 20 to 40 minutes. Suitablealkyl lithiums include methyl lithium, ethyl lithium, n-propyl lithiumand n-butyl lithium; and preferably n-butyl lithium. Suitable iodooctenol ethers which can be used, either as racemic (dl) mixtures or asthe pure (R) or (S) optically active isomer, are those having theformula:

c G urchin CH (CH V) CH wherein the (c) over the double bond indicatesthe cis configuration; OR is selected from the group consisting of acidlabile ethers having from three through 10 carbom atoms; and the wavybond line indicates an asymmetric carbon center and indicates both the(dl) racemic mixture or the individual (R) or (S) optically activeisomer.

Also, mixtures of the (dl)-l-iodo-cis-locten-3-ol 3- ether;(R)-liodo-cis-I-octen-3-ol 3-ether and (S)-liodo-cis-l-octen-Zi-ol3-ether can be used, though typically this would not be desirable as theprimary advantage of the optically active (R)- reagent and (S)- reagentis their (stereochemical) selectivity; which would be wasted by mixturewith the (dl)-reagent or with each other. Accordingly, the pure(R)-l-iodo-cis- 1*octen-3-ol 3-ethers and pure (S)-1-iodo-cis-1-octen-3-ol 3-ethers are preferred. Also, mixtures of different 3-ethers couldbe used, for example, (S)-l-iodo-3-(2'- methoxyprop-2-oxy)-cis-l-octeneand (S)-l-iodo-3- (tetrahydropyranyl-2-oxy)-cis-l-octene.

The preferred iodo octenol ethers are:

(d1)-l-iodo-3-(2-methoxyprop-2-oxy)-cis-l-octene;

(S)-l-iodo-3-(2'-methoxyprop-2'-oxy)-cis-l-octene;

(d1)-l-iodo-3-(tetrahydropyranyl-2'-oxy)-cis-loctene;

(R)-l-iodo-3-(tetrahydropyranyl-Z'-oxy)-cis-loctene; and

(S 1 -iodo-3-(tetrahydropyranyl-2 -oxy)-cisl octene.

Accordingly because of the isomeric selectivity, the particularlypreferred iodo octenol ethers are:

(R)-l-iodo-3-(2methoxyprop-2'-oxy)-cis-l-octene;

(S)- l -iodo-3-(2-methoxyprop-2-oxy)-cisl octene;

(R)-l-iodo-3-(tetrahydropyranyl-Z'-oxy)-cis-loctcnc;

(S l Judo-34 tctrahydropyranyl-2oxy )-cisl octcne:

(R l -iodo-3-methoxymethoxy-cis-l-octene; and

(S)-liodo-3-methoxymethoxy-cis-loctene.

Also, as previously noted, the 3-(2-methoxyprop-2- oxy) reagents willyield prostaglandin ether derivatives having very easily cleavableIS-ether groups.

Also, as this treatment and also subsequent treatments can be conductedat substantially reduced temperatures, it is necessary that the inertorganic solvent have a melting point below the particular treatmenttemperature used, to ensure that the liquid state is retained. Suitablesolvents include alkane solvents having a melting point below theparticular treatment temperature used. Thus, by increasing the treatmenttempera tures, a slightly broader range of solvents can be used.Suitable alkane solvents which are operable throughout the to C rangeinclude, for example, pentane, hexane, heptane and the like. Typically,best results are obtained using hexane.

The copper component solution can be prepared by dissolving a copper"halide salt in a suitable inert organic solvent. Typically, thetreatment is conducted at about from 0 to 30C. The particulartemperature used is not critical with respect to this treatment,however, as the ultimate mixing step can be conducted at reducedtemperatures (i.e. l00 to 20C) it is necessary that the inert solventhave a melting point below the temperature used in the ultimate mixingstep. Suitable solvents include ether solvents having melting pointsbelow the temperature used in the ultimate mixing step. Suitable ethersolvents include, for example, diethyl ether, methyl ethyl ether, andthe like. Best results are typically obtained using diethyl ether.Suitable copper halides which can be used include copper" iodide,copper" fluoride, copper" chloride, and copper" bromide. Best resultsare obtained using copper" iodide. Typically, a copper" halide saltsolvent concentration in the range of about from 0.5 to 50 wt. percent,preferably 2 to 10 percent, is used, though again this is largely amatter of convenience and concentrations both above and below this canalso be used.

As noted above, the complexing reagent must be present, in particularone of the sub-component solutions, prior to their admixture together.Thus, where a combination complexing reagent-copper" halide (e.g.bis-(trimethylphosphite)copper" iodide) is used, the complexing reagentis inherently present in the copper" sub-component solution and thecopper component solution can be prepared in the same manner asdescribed above but merely replacing the copper" halide with thecombination complexing reagent copper halide.

Where a trialkyl phosphite or trialkyl phosphine complexing reagent isused, the complexing agent is added to the copper" halide solution. Thisaddition can take place either before or after the addition of thecopper" salt to the solvent and typically the copper" salt and phosphiteor phosphine complex are added at about the same time. Suitablephosphite and phosphine complexing agents include trimethyl phosphite,triethyl phosphite, tri(n-propyl)phosphite, and tri(nbutyl)phosphite;trimethyl phosphine, triethyl phosphine, tri(n-propyl)phosphine, andtri(nbutyl)phosphine. Typically, better results are obtained with thephosphite complexing reagents than the phosphine complexing reagents.The preferred phosphite complexing reagent is trimethyl phosphite andthe preferred phosphine complexing reagent is tri(nbutyl)phosphine.

Where a diaminetype complexing reagent (e.g. tetraalkylalkylenediamines;naphthalene bridge diamines, alkylpiperazines and the like) is used, thecomplexing agent is added to the octenol'ether lithium solution and mustbe added to the product solution (i.e. after the addition of the desiredalkyl lithium and iodo cis-octenol ether and after the solution has beenallowed to stand as described above). In this case, the addition ofcomplexing agent is typically conducted at temperatures in the range ofabout from -l00 to 20C, preferably in the range of about from to 0C forabout from 20 to 40 minutes. Preferably, the diamine complexing agent isa tetraalkylalkylenediamine, as previously described. Best results aretypically obtained using N,N,- N,N-tetramethylethylenediamine.

Where the copper" iodide solution contains the complexing reagent, thefinal mixing treatment can be conducted by admixing the octenol etherlithium solution and copper" halide solution at temperatures in therange of about from 80 to 0C for about from 5 minutes to 6 hours.Preferably, the treatment is conducted at a temperature of about 40C forabout from 5 minutes to 6 hours. Also, it is preferable to cool thecopper salt solution to the mixing temperature range if it is notalready within the temperature range.

Where the octenol ether lithium solution contains the complexing reagent(e.g. diamines), the final mixing treatment can be conducted by addingthe octenol ether lithium solution to the copper" halide solution attemperatures in the range of about from l00 to 20C, preferably aboutfrom -80 to 0C. After the initial admixture, the temperature isincreased to about from fi0iita9jCs rsferab bate. 107C and maintained atthis temperature for about from 5 minutes to 6 hours, preferably aboutfrom 20 to 40 minutes. Also, in this case, the copper" halide solutionshould be precooled to about from l00 to 20C, preferably about -80 to 0C(if it is not already within this temperature range) prior to theaddition of the octenol ether lithium solution.

Where a tri(alkyl)phosphite or tri(alkyl)phosphine complexing agent isused, it is preferable to admix respective sub-component solutions inrelative proportions to provide an ultimate mixture having the followingratio of components (based on initial starting materials) per mole ofiodooctenol ether:

1 mole of alkyl lithium;

0.05 to 2 moles of copper halide;

0.1 to 4 moles of trialkyl phosphite or trialkyl phosphine. Best resultsare obtained wherein the final mixture, based on initial startingmaterials, contains about 1 mole of alkyl lithium; about 0.5 mole ofcopper" halide; and about 1 mole of trialkyl phosphite or trialkylphosphine per mole of iodooctenol ether.

Where a tetraalkylalkylenediamine complexing agent is used. therespective solutions should be admixed in relative ratios to provide anultimate mixture having about the following ratio of components (basedon initial starting materials) per mole of iodooctenol ether:

1 mole of alkyl lithium;

0.05 to 2 moles of copper halide;

0.l to 4 moles of tetraalkylalkylenediamine.

Best results are obtained using about 1 mole of alkyl lithium; about 0.5mole of copper halide and about from 0.5 to 1 mole oftetraalkylalkylenediamine per mole of iodooctenol ether.

Where bis-(trimethylphospshite) copper" iodide is used. it is preferablethat the respective solutions are admixed in relative proportions toprovide an ultimate mixture having about the following ratio ofcomponents (based on initial starting materials) per mole of iodooctenolether:

1 mole of alkyl lithium;

0.05 to 2 moles of bis-(trimethylphosphite) copper" iodide. Best resultsare obtained using about one mole of alkyl lithium and about 0.5 mole ofbis- (trimethylphosphite) copper iodide per mole of iodooctenol ether.

The process, of the invention, for preparing the 9- oxo-l3cisprostaglandin derivatives of the invention can be schematicallyrepresented by the following overall reaction equation:

(CH coon 1 (CH2) coca group of said complexed octenol ether copper"lithium reagent and the line indicates either the a or ,8 configurationor mixtures of isomers having the a and [3 configuration; and the wavylines at the C-8, C-l 1 and C-l2 positions indicate the a and Bconfiguration and wherein the substituents at C-8 and C-l2; and C-ll andC-l2 are trans to each other (i.e. have opposite configurations).

The process can be effected by treating the appropriate startingmaterial of formula A, having the desired R substituent and side chain,with the complexed cis-octenol ether copper" lithium reagent of ourinven tion under reactive conditions. The treatment can be conducted attemperatures in the range of about from -lOO to 20C, preferably aboutfrom to 0C for about from 5 minutes to 24 hours. Preferably, thetreatment is conducted by adding a solution of the cyclopentenonestarting material of formula A, in a suitable inert organic solvent,directly to the reagent of our invention. Suitable inert organicsolvents include, for example, diethyl ether, methyl ethyl ether and thelike. Also, substantially superior results are obtained by using freshlyprepared complexed octenol ether copper lithium reagents.

Our process affords the important advantage that the octenyl 3-etherside chain attaches to the cyclopentane moiety at an oppositeconfiguration to the carboalkoxyhexyl side chain (i.e. 04,,8 or 3,01),thus enhancing isomer selectivity and eliminating the undesiredbyproduct isomers wherein the side chains have the same configuration,i.e. a,a, or ,Bfi and in addition affords high yields as compared withconventional prostaglandin sythesis.

We have surprisingly found that the use of racemic reagent willtypically yield a product which is in effect stereo specific withrespect to the C-1 5 position in contrast to the diastereomeric 15aandISB-isomer mix-' ture, which one would expect. Thus, we have found thatthe use of (dl)-liodo-cis-l-octen-3-ol 3-ether derived reagent willyield the corresponding enantiomeric l5B-ether-l3-cis prostanoic acidester (e.g. formula III) and retro-l5a-ether-l3-cis prostanoic acidester (e.g. formula lllr), with no or only negligible quantities of thecorresponding 1501- and retro-l5B-ethers (e.g. formulas IV and lVr).Further, when a pure optically active (R)-iodo-cis-l-octen-3-ol 3-etheror pure optically active (S)-iodo-cis-l-octen-3-ol 3 ether derivedreagent is used, the respective products will be single enantiomers.Thus, the optically active (R) reagent will yield the correspondingISB-ether-l 3-cis prostanoic acid ester i.e. (R)-stereochemistry at C-l5(e.g. formula lll) and the optically active (S) reagent will yield thecorresponding retro-l5a-ether-l3-cis prostanoic acid ester i.e.(S)-stereochemistry at C-l5 (e.g. formula lllr). Hence, by using a pureoptically active (R) or (S) reagent, isomer product mixtures areprecluded.

Where other isomeric products are desired (e.g. formula IV and lVr),these products can be obtained by epimerization via solvolysis of thecorresponding 15B- and retro-l5a-ether-l3-cis prostanoic acid esters(e.g. formulas Ill and lllr), respectively. We have found that in thecase of the compounds of formula I wherein R is hydrogen that this canbe conveniently effected by solvoylsis according to the followingschematic overall reaction sequence:

1" (CH2) c 12 wherein R is as defined herein above, Ms ismethanesulfonyl, and the substituents indicated at C8 and C-l2 by thewavy lines are trans to each other.

In the first step of this treatment, the ISB-hydroxy substituent ismesylated or tosylated via any suitable procedure. For example, this canbe effected by treatment with methanesulfonyl chloride in a suitableinert organic solvent (e.g. methylene chloride), typically attemperatures in the range of from about 40 to C for about from 10minutes to 2 hours. Also in place of methanesulfonyl chloride, otherlower alkanesulfonyl chlorides or phenylsulfonyl chlorides could also beused. The resulting mixture is then preferably merely allowed to rise toaround room temperature, washed with water yielding a two phasewater-methylene chloride product fraction. The methylene chlorideproduct fraction is separated and then treated (step 2) with aqueousacetone. The treatment is typically conducted at temperatures in therange of about from 10 to 30C, conveniently room temperature, for aboutfrom 2 to 48 hours, preferably about 12 to 24 hours. As can be seen (CHC0 13 (0H co (CH2) co from the above reaction equation, the resultingproduct is a mixture of the corresponding 15a and 15B isomers. Thetreatment can be applied to both pure enantiomers and mixtures ofenantiomers. Typically, the ratio of l5ato 153- is in the range of about:60 to :40. Where a racemic pair of enantiomers is used as the startingmaterial for the solvolysis, the product will be a mixture of twodifferent racemic pairs of enantiomers. Further, variation in the ratiomix can be obtained, if desired, by adding the desired pure 15a or 153isomers (prepared by the use of optically active reagents as describedabove) to the product.

Where it is desired to prepare 1501-, ISB-isomer mixtures having ahydroxy function at C-l 1 (Le. R is hydroxy) via this route, it ispreferable to prepare a l3-cis prostaglandin having an easily cleavableacid labile ether at C-l5 (e.g. OR is 2'-methoxyprop-2'-oxy) and a morestable acid labile ether at C-ll (e.g. R is tetrahydropyranyI-Z-oxy).The epimerization can then be conducted according to the followingschematically 40 represented process:

(cn l co n 3 --n THP 'ggz' s OTHP OH 1" (CH2) c0 12 (cs c0 12 OTHP O'IHPOH OTHP (CH (30 R 1 7 18- wherein OTHP is tetrahydropyranyl-Z-oxy;hydroxy epimers can be separated according to coni thanegulfonyl Oxy orival t group; ventional procedures such as, for example, column and R ias d fi d h i b chromatography. Thus, where pure enantiomers are Th fi tstep i hi treatment can b ff d i any desired, it is preferable to usepure enantiomer starting suitable acid hydrolysis treatment sufficientlymild to 5 materials in Order to minimize the number of enantiocleave theether group at C-l5 (shown as methoxy- 1116f P oducts and facilitateseparation. propoxy for convenience) without cleaving the ether Thepective acid labile ether groups at C-l l dgroup at C-1 1 (shown astetrahydropyranyloxy for /r C-l can be removed by conventional mild acidhy- Convehience) h case f C 15 methoxypropoxy drolysis. Thus, forexample, the ether groups can be and 3-1 1 tetrahydropyranyloxy, hi canb come. conveniently removed via treatment with 50 to 75 pernientlyeffected by treatment with aqueous acetic acid C nt Wt. aqueous aceticacid at temperatures in the (typically 10 to 25 percent wt.) at aboutfrom 0 to rang 0f a out from to 50C, conveniently room 40C, typically atroom temperature, for about fr 1 temperature, for about from 5 to 48hours. The acids to 60 minutes. The remaining steps (i.e. mesylation andR1 is y g of formula I Can be prepared by solvolysis) can be conductedas described above with 15 ea ing the Corresponding R -esters. This canbe c respect to the C-ll hydrogen (R is hydrogen) l3-cis venientlyeffected via any suitable microbiological enprostaglandin derivatives.zymatic procedure for cleaving ester groups. A pre- The PGF series ofthe 13-cis prostaglandin derivaferred non-limiting enzymatic hydrolysisprocedure is, ti f f l 1 can b pmpared i d ti f th for purposes ofillustration, described herein below in corresponding PGE (R isoxo)-l3-cis prostaglandin Example 10. derivatives: Throughout the abovedescribed processes where o l on OH I (CH CO R (CH (19 R (CH CO R R R Rwherein R, R and OR and the wavy lines are as depure optically activeisomeric products are desired, it fined hereinabove. is preferable touse the appropriate optically active (R) The respective9,15-dihydroxy-prost-l 3-enoic acids or (S) reagents and to conduct thevarious substituent and lower alkyl esters can be prepared by reducingthe modifications in a sequence to obtain pure enantiocorresponding9-oxo function to the corresponding 9- meric products or di tereo i od ta nhydroxy function. This can be conveniently effected by trasted toracemic products; since the respective diastreatment with sodiumborohydride in a suitable inert tereomeric isomers can be separated byrelatively simorganic solvent (e.g. methanol). Typically this treatpierocedures, e.g. chromatography, in contrast to the ment is conducted attemperatures in the range of more difficult and complex proceduresrequired to sepabout from 0 to 25C for about from one to ten hours.arate racemic mixturs. Illustrations of typical non- Also in place ofmethanol, other suitable solvents limiting diastereomeric separationprocedures can be which can be used include, for example, tetrahydrohadby reference to the appropriate Examples set forth furan, dioxane, etc.,and the like. Since the reduction herein below.

is not selective, the number of isomers in the product Because of thehigh yields of l3-cis prostaglandin reaction mixture will be double thatin the starting maproducts, which are obtained by our process, we haveterial because of the introduction of the asymmetric found that bysubsequently rearranging the 13-cis doucenter at C-9. Thus, where pureIS-a-hydroxy or lS-B- ble bond that we have obtained a felicitousprocess for hydroxy starting materials are used. the resultingprodpreparing prostaglandin products having the natural uct will be amixture of the corresponding 9aand 9B- l3-trans orientation. Thisprocess can be represented hydroxy epimers. The resulting pure 9aand9/3- by the following schematic reaction sequence:

(on coon (car coon 2 n 2 n (:11) z b OR R OH H (CH COOR CH COCJR 45L. RR

wherein n, R" R R, OR and the wavy lines are as defined herein above.

Step 1, the initial preparation of the 9-oxo-l3-cis prostanoic acidderivation, is conducted as previously described. Where the PGF seriesis desired, the x0 group can be reduced to a hydroxy group via step lawhich can be conducted as previously described. The reduction step canbe conducted either before or after the rearrangement step (2). Therearrangement step (step 2) can be conducted according to conventionalrearrangement steps and is generally easily effected since the l3transorientation is the favored orientation and is in fact the orientationwhich occurs in nature. The rearrangement can, for example, beconveniently wherein OR is as defined herein above; the wavy lineindicates either the optically (R) or (S) isomer or a racemic mixturethereof;' and the (c) over the double bond indicates the cisconfiguration.

The (S)-l-octyn-3-ol starting materials can be prepared by knownprocedures such as, for example, described by Fried et al in Ann. N.Y.Acad. Sci., V. 180, p. 38 (1971). The (R)-1-octyn-3-ol starting materialcan be prepared according to the same procedure by using the(+)-a-phenethylamine in place of (-)-aphenethylamine.

The starting materials of formula A wherein R is hydrogen can beconveniently prepared according to the following schematic overallreaction equation seeffected by treating the corresponding l3-cis pros-15 quence;

o OAC 1" ill (CH COOR I J: (CH CO R 2 i (A a g (A (CH2) co R I (CH2) c012 2' (A (A, R 13 H) tenoic acid, or preferably an ester thereof, with asuitable free radical initiator (e.g. diphenyldisulfide) in a suitableinert organic solvent (e.g. benzene) and irradiation with visible wavelength light (e.g. conventional sun lamp). In the case of thell-hydroxy-l3-cis prostenoic acids (preferably esters), it is preferableto first protect the l l-hydroxy substituents, and any other hydroxysubstituents which are present, with a tetrahydropyranyloxy group, orother suitable ether groups, prior to rearrangement (step 2). The etherand ester groups can then be cleaved, if desired, in the same manner asdescribed herein above with respect to the l3-cis prostaglandin acidderivatives.

STARTING MATERIALS The l-iodo-cis-l-octen-3-ol 3-ethers, used in thepreparation of the reagent, of the invention, can be prepared by thefollowing schematically represented overall reaction equation sequence:

wherein R and n are as defined above; and Ac is a conventional labileacyl, preferably acetyl.

Step 1 of the above preparation can be conveniently effected by treatingthe compounds of formula A' with isopropenyl acetate in the presence ofan acid catalyst. This treatment should be conducted under anhydrousconditions and is typically conducted at the boiling point ofisopropenyl acetate until the reaction is complete, usually from 3 to 12hours. Typically, a large excess of isopropenyl acetate is used. Also inplace of isopropenyl acetate, other suitable reagents can be used, forexample, acetic anhydride, propionic anhydride and the like. Suitableacid catalysts which can be used include, for example, mineral acidssuch as, for example, sulfuric acid and the like and organic acids suchas, for example, p-toluenesulfonic acid or oxalic acid. The compounds offormula A are known compounds or can be prepared according to knownprocedures. For example, compounds of formula A can be prepared by thegeneral procedure described by Bagli et al. in Tetrahedron Letters,465-470 (1966), but substituting a bromocarboxylie ester of theappropriate chain length in place of ethylw-bromoheptanoate where astarting material, of formula A, is desired having a chain length otherthan n is 6 is desired.

Step 2 of our preparation is conveniently effected by treating thecompounds of formula A with N- bromoacetamide or N-bromosuccinimide in asuitable inert organic solvent. Typically, this step is conducted attemperatures in the range of about from l to 25C for about from fiveminutes to three hours. Preferably the reaction solution is monitored,for example, by thin-layer chromatography, to ensure that the startingmaterial of formula A is consumed before starting the third step. Instep 3, the initial reaction mixture is treated with a suitable basesuch as, for example, lithium carbonate in pyridine. This phase istypically conducted at temperatures in the range of about from 50 1 NBSaqu. AgClO (CH2) COOR 1 l (CH COOR wherein R and the wavy lines are asdefined herein above; and R is an acid labile ether having from threethrough ten carbon atoms.

The first step of this process is conveniently conducted in two phasesand can be conveniently effected by treating the desired2-(carboalkoxy-alkyl)-l-oxocyclopent-Z-ene with N-bromosuecinimide orequivalent reagent (e.g. N-bromoacetamide, N,N- dibromoacetamide, etc.)in a suitable inert organic solvent (e.g. carbon tetrachloride) followedby irradiation of the mixture with visible wave length light and thentreating the product with silver perchlorate in a suitable aqueous inertorganic solvent. Considering this treatment as two phases, the firstphase is typically conducted at temperatures in the range of about from0C to the boiling point of the solvent for about from to 2 hours.Suitable inert organic solvents which can be used include, for example,carbon tetrachloride, and the like. Tyipcally, a mole ratio in the rangeof about from slightly above 12 moles of N-bromosuccinimide per mole ofcyclopentenone derivative starting material is used.

With respect to the irradiation light, any suitable source of visiblelight can be used, for example, conventional sun lamps.

The second phase of this step can be conveniently effected by treatingthe brominated product of the first phase with silver perchlorate in asuitable aqueous inert organic solvent. Typically, this phase isconducted at temperatures in the range of about from 0 to C, preferablyabout from 10 to 35C for about from to 2 hours. Suitable aqueous inertorganic solvents which can be used include, for example, aqueousacetone, aqueous tetrahydrofuran, aqueous dioxane, and the like. Also,preferably the crude brominated product is separated from the firstphase reaction mixture prior to conducting the second phase.

The next step, the addition of the ether group, can be effected via anysuitable procedure for selectively protecting a hydroxy group, inpreference to an oxo group, with the desired ether group. Thus, forexample, this can be conveniently obtained by treating the 2-(carboalkoxy-alkyl)-4-hydroxy-l-oxo-eyclopent-2-ene product with thedesired ether (e.g. isopropenyl methyl ether, dihydropyran, etc.) in thepresence of an acid catalyst (e.g. phosphorous oxychloride,p-toluenesulfonic acid, etc.). Typically, this treatment is conducted attemperatures in the range of about from 15 to 30C, conveniently at roomtemperature for about from /2 to 4 hours. Optionally, an inert organicsolvent can also be used, though the ether reagent will itself alsoserve as solvent.

1 l (CH c0012 Isolation of the intermediates and products can beeffected by any suitable separation or purification procedure such as,for example, extraction, filtration, evaporation, crystallization, andthin-layer chromatography. Specific illustrations of typical separationand isolation procedures can be had by reference to the examplesdescribed herein below. However, other equivalent separation orisolation procedures could, of course, also be used.

The prostaglandin products and prostaglandin derivative products of theabove processes exhibit prostaglandin-like biological activities andthus are useful in the treatment of mammals where the use ofprostaglandins are indicated. The compound (and pharmaceuticallyacceptable salts) are bronchodilators and thus are useful in tratingmammals for bronchial spasm or wherever strong bronchodilators areindicated. The compounds are also useful in controlling or palliatinghypertension in mammals and further exhibit central nervous systemdepressant activity, in mammals, and are useful as sedatives. Inaddition, the compounds are useful for inducing labor, in pregnancy, andfor inducing menses to correct or reduce menstrual abnormalities. Thecompounds also possess anti-fertility properties. The l3-cis compoundsalso exhibit anti-inflammatory activites and thus are useful asanti-inflammatory agents.

These compounds can be administered in a wide variety of dosage forms,either alone or in combination with other pharmaceutically compatiblemedicaments, in the form of pharmaceutical compositions suited for oralor parenteral administration or inhalation in the case ofbronchodilators. The compounds are typically administered aspharmaceutical compositions consisting essentially of the compoundsand/or salts, of the invention, and a pharmaceutical carrier. Thepharmaceutical carrier can be either a solid material, liquid, oraerosol, in which the compound and/or salt is dissolved, dispersed orsuspended, and can optionally contain small amounts of preservativesand/or pH- buffering agents. Suitable preservatives which can be usedinclude, for example, benzyl alcohol and the like. Suitable bufferingagents include, for example, sodium acetate and pharmaceutical phosphatesalts and the like.

The liquid compositions can, for example, be in the form of solutions,emulsions, suspension, syrups, or elixirs. The solid compositions cantake the form of tablets, powders, capsules, pills or the like,preferably in unit dosage forms for simple administration or precisedosages. Suitable solid carriers include, for example, pharmaceuticalgrades of starch, lactose, sodium saccharin, talcum, sodium bisulfiteand the like.

For inhalation administration, the compounds can, for example, beadministered as an aerosol comprising the compounds or salts in an inertpropellant together with a cosolvent (e.g. ethanol) together withoptional preservatives and buffering agents. Additional generalinformation concerning the inhalation administration of aerosols can behad by reference to US. Pat. Nos. 2,868,691 and 3,095,355.

The compounds are typically administered in dosages of about from O.l tomg. per kg. of body weight. The precise effective dosage will, ofcourse, vary depending upon the mode of administration, condition beingtreated. and host.

A further understanding of the invention can be had from the followingnon-limiting preparations and examples. Also, where necessary,preparations and examples are repeated to provide starting materials forsubsequent preparations and examples.

PREPARATION 1 This preparation illustrates methods of preparing(dl)-l-iodo-cis-l-octen-3-ol. In this preparation 22 ml. of 1.5M n-butyllithium in hexane is added to a mixture containing 6.3 g. of(dl)-3-(tetrahydropyranyl-Z'-oxy)- l-octyne (prepared by the acidcatalyzed treatment of (dl)-l-iodo-l-octyn-3-ol with dihydropyran), in100 ml. of diethyl ether at 78C, under a nitrogen atmosphere, withconstant stirring. After 30 minutes a mixture containing g. of iodine in70 ml. of diethyl ether is added and the resulting mixture warmed toroom temperature. The mixture is then treated with 5 percent aqueoussodium thiosulfate solution to consume excess iodine, resulting in theformation ofa two phase liquid-liquid system. The ether layer isseparated and washed with saturated aqueous sodium chloride solution andthen evaporated to dryness, under vacuum, yielding a crude residue of(dl)-l-iodo-3- (tetrahydropyranyl-Z-oxy)-l-octyne. The residue isdissolved in ml. of methanol and added to 20 g. of dipotassiumazodicarboxylate. Fifteen milliliters of acetic acid is slowly addeddropwise over a period of about one hour. The reaction mixture ismonitored by vapor phase chromatography to ensure that the reaction hasgone to completion and then filtered and concentrated by vacuumevaporation to a volume of approximately 30 ml. The concentrate ispoured into 300 ml. of water and the resulting mixture extracted withfour 50 ml. portions of diethyl ether. The ether extracts are combinedand evaporated to dryness under vacuum. The residue is stirred for 16hours with 20 ml. of a 40 percent aqueous dimethylamine mixture and thenpoured into 100 g. of ice yielding a two phase liquidliquid mixture. Theaqueous phase is made slightly acid by the addition of 4M aqueoushydrochloric acid. The mixture is then extracted with four 50 ml.portions of diethyl ether. The ether extracts are combined and shakenwith 50 ml. of aqueous saturated sodium chloride solution, and thenevaporated under vacuum to remove the ether solvent. The resultingresidue is stirred with 40 ml. of aqueous 65 percent dichloro aceticacid for two hours at room temperature and then poured onto 100 g. ofice. The mixture is then made slightly basic by the controlled additionof aqueous 15 percent sodium hydroxide solution and extracted with four50 ml. portions of diethyl ether. The ether extracts are combined andconcentrated by vacuum evaporation affording a residue which ischromatographed over a mixture containing 250 g. of silica gel and 5 g.of powdered copper, eluting with 10 percent ethyl acetatehexanemixtures, yielding (dl) l-iodo-cis-l-octen-3-ol. .fSiHt arIY. -i. ;9ir.1:9tn- -0 and (S)-l-iodo-cis-l-octen-3-ol are respectively preparedaccording to the same procedure but respectively replacing(dl)-3-(tetrahydropyranyl-2-oxy)-l-octyne with(R)-3-(tetrahydropyranyl-2'-oxy)-l-octyne and (S)-3-(tetrahydropyranyl-2-oxy)-1-octyne.

PREPARATION 2 This preparation illustrates additional methods ofpreparing 3-ethers of (dl)-; (R)- and (S)-l-iodo-cis-locten-3-ol. Inthis example a small drop of phosphorous oxychloride is added to amixture containing 2.71 g. of (dl)-l-iodo-cis-l-octen-3-ol and 5 g. ofisopropenyl methyl ether. The mixture is maintained in a closed reactionvessel for 45 minutes at room temperature and then three drops oftriethylamine is added and the resulting mixture evaporated by vacuumevaporation affording a residue of pure (dl)-l-iodo-3-(2- methoxyprop-2'-oxy )-cisl -octene.

Similarly, by following the same procedure but respectively usingn-butyl ispropenyl ether and pentylcyclohexenyl ether in place ofispropenyl methyl ether, the following compounds are respectivelyprepared:

(dl)-l-iodo-3-(2'-butoxyprop-2'-oxy)-cis-l-octene; and

(dl)- l -iodo-3-( l-pent-l "-oxycyclohexyl-l -oxy cis-l-octene.

Similarly, by following the same procedure but respectively replacing(dl)-l-iodo-cis-l-octen-3-o| with (R)-l-iodo-cis-l-octen-3-ol and(S)-l-iodo-cis-locten-3-ol, the following optically active compounds arerespectively prepared:

(R)-l-iodo-3-(2-mcthoxyprop-2'-oxy)-cis-l-octene;

(S)-l-iodo-3-(2'-methoxyprop-2-oxy)-cis-l-octenc;

(R)-l-iodo-3-(2'-butoxyprop-2-oxy)-cis-l-octcne;

PREPARATION 3 This preparation illustrates further methods of preparing3-ethers of (dl)-; (R) and (S)-l-iodo-cis-locten-3-ol. In this example5.05 g. ofa 56 percent (wt.) dispersion of sodium hydride in mineral oilis washed with two 100 ml. portions of pentane, followed by decantationto remove excess pentane. 125 Ml. of tetrahydrofuran is then added andthe resulting mixture is maintained under nitrogen. A solutioncontaining 25.4 g. of (dl)-l-iodo-cis-1-octen-3-ol in I25 ml. ofanhydrous tetrahydrofuran is then slowly added over a 30 minute periodand the resulting mixture refluxed for an additional 30 minutes. Afterthis time a solution copntaining 12.5 g. of 2-chlorotetrahydropyran in50 ml. of anhydrous tetrahydrofuran is slowly added over a minute periodand the resulting mixture refluxed for an additional hour, and thencooled to room temperature and added to 500 ml. of water, followed byextraction with three 100 ml. portions of diethyl ether. The combineddiethyl ether fractions are dried over potassium carbonate, filtered,and the resulting filtrate evaporated to dryness affording a cruderesidue of (dl)-liodo-3-(tetrahydropyranyl-2'-oxy)-cis-l-octene, whichis then further purified by chromatography on 1,000 g. of silica geleluting with percent ether-hexane mixture.

Similarly, by respectively replacing 2-chlorotetrahydropyran witha-chloroethyl phenyl ether and a-chloroethyl ethyl ether, the followingcompounds are respectively prepared:

(dl)-l-iodo-3a-phenoxyethoxy-cis-l-octene; and

(d1)- 1 -iodo-3-( l'-ethoxyethoxy)-cisl -octene.

Similarly, by following the same procedure but respectively using(R)-l-iodo-cis-l-octen-3-ol and (S)-l-iodo-cis-1-octen-3-ol in place of(dl)-l-iodo-cisl-octen-3-ol, the following optically active compoundsare respectively prepared:

(R)-1-iodo-3-(tetrahydropyranyl-2-oxy)-cis-loctene;

(S)-l-iodo-3-(tetrahydropyranyI-Z'-oxy)-cis-loctene;

(R)-l-iodo-3a-phenoxyethoxy-cis-l-octene;

(S)-l-iodo-3-a-phenoxyethoxy-cis-l-octene;

(R)-l-iodo-3-( l '-ethoxyethoxy)-cis-l-octene; and

(S l -iodo-3-( l'-ethoxyethoxy )-cisl -octene.

PREPARATION 4 This preparation illustrates methods for preparinglacy|oxy-2-(carboalkoxy-alkyl)-cyclopent-l-ene. In this example, 26.5 g.of 2-(6-carbomethoxy-hexyl)-l-oxocycxlopentane is added to 250 ml. ofisopropenyl acetate containing 0.4 ml. of concentrated sulfuric acid.The mixture is then slowly distilled for 2 /2 hours and then cooled toroom temperature and poured into an iced saturated solution of aqueoussodium bicarbonate. The mixture is then extracted with methylenechloride. The methylene chloride extract is washed with water and thenwashed with saturated brine, then dried over anhydrous sodium sulfateand evaporated to dryness affording a crude residue of l-acetoxy-2-(6-carbomethoxyhexyl)-cyclopent-l-ene, which is further purified by highvacuum distillation.

Similarly, by following the same procedure but re spectively using thecorresponding 2-(carboalkoxyalkyl)-l-oxo-cyclopentane startingmaterials, the following compounds are respectively prepared:

l-acetoxy-2-( 6-carboethoxy-hexyl )-cyclopentl -ene;

l-acetoxy-2-( 6-carbohexoxy-hexyl )-cyclopent l-ene;

l-acetoxy-2-(2-carbomethoxy-ethyl)-cyclopentl-ene;

l-acetoxy-2-(2-carboethoxy-ethyl)-cyclopent-l-ene;

l-acetoxy-2-( 2-carbohexoxy-ethyl)-cyclopentl -ene;

l-acetoxy-2-(8-carbomethoxy-octyl)-cyclopent l-ene;

l-acetoxy-2-( 8-carboethoxy-octyl)-cyclopent- 1 -ene;

and l-acetoxy-2-( 8-carbohexoxy-octyl )-cxyclopentl-ene.

PREPARATION 5 This preparation illustrates methods of preparing 2-(carboalkoxy-alkyl)-l-oxo-cyclopent-2-ene. In this example 20.1 g. ofcrude l-acetoxy-2-(6-carbomethoxyhexyl)-cyclopent-1-ene, preparedaccording to Preparation 4, is dissolved in 180 ml. of tetrahydrofuranand 20 ml. of water and then cooled to 0C under nitrogen. Eleven gramsof N-bromoacetamide is added. The resulting reaction solution ismonitored by thin-layer chromatography and allowed to stand untilcomplete reaction is indicated. The reaction mixture is then poured intowater and extracted with methylene chloride. 150 Milliliters of pyridineand 3 g. of lithium carbonate are added to the methylene chlorideextract and the resulting mixture then concentrated by evaporation underreduced pressure to remove most of the methylene chloride. Theconcentrate is stirred at C under nitrogen, for 1 hour and then examinedby thin-layer chromatography to ensure complete reaction. The reactionsolution is then cooled to room temperature and poured into water andextracted with methylene chloride. The methylene chloride extract iswashed with water, washed with saturated aqueous sodium chloride, thendried over sodium sulfate, and evaporated to dryness affording a cruderesidue of 2-(6-carbomethoxyhexyl)- l -oxo-cyclopent-2-ene, which isfurther purified by high vacuum distillation. This product is thendissolved in 350 ml. of methanol, and a solution containing 4.6 g. ofsemicarbazone hydrochloride and 5 g. of pyridine in 40 ml. of water isthen added. The resulting mixture is stirred at room temperature for 2hours and then poured into water. The water mixture is filtered, and thecollected precipitate is washed with hexane. The filtrate and washingsare combined and extracted four times with hexane. The extracts arecombined and washed with water, washed with saturated aqueous sodiumchloride solution, and then dried over sodium sulfate and evaporated todryness affording pure 2-(6- carbomethoxy-hexyl l -oxo-cyclopent-2-ene.

Similarly, by following the same procedure but respectively using thecorresponding products of Preparation 4 as starting materials, thefollowing compounds are respectively prepared:

2-(6-carboethoxy-hexyl)-l-oxo-cyclopentQ-ene;

2-(6-carbohexoxy-hexyl)- l -oxo-cyclopent-2-ene;2-(2-carbomethoxy-ethyl)-l-oxo-cyclopent-Z-ene;2-(2-carboethoxy-ethyl)-l-oxo-cyclopent-2-ene;2-(2-carbohexoxy-ethyl)-l-oxo-cyclopent-Z-ene;

2-( S-carbomethoxy-octyl l -cyclopent-2-ene;

2-(8-carboethoxy-octyl)-l -oxo-cyclopent-2-ene; and

2-(8-carbohexyoxy-octyl)-l-oxo-cyclopent-2-ene.

PREPARATION 6 This preparation illustrates methods of preparing 4-ethers of 2-(carboalkoxy-alkyl)-l-oxo-cyclopent- 2-ene. In this examplea mixture containing 4.23 g. of2-(6-carbomethyoxy-hexyl)-1-oxo-cyclopent-2-ene and 3.36 g. ofN-bromosuccinimide in 100 ml. of carbon tetrachloride is irradiated withvisible light (using a 150 watt Photo-Flood lamp) for 20 minutes at Cunder nitrogen. The mixture is allowed to cool to room temperature andthen filtered and the resulting filtrate evaporated, under vacuum, todryness. Fifty milliliters of 1:1, by vol.,' acetone-water mixturecontaining g. of silver perchlorate is then added to the residue and theresulting mixture allowed to stand for about minutes at roomtemperature. The mixture is concentrated by evaporation under reducedpressure to remove most of the acetone and the resulting concentrateextracted four times with 100 ml. portions of ethyl acetate. The ethylacetate extracts are combined and sequentially washed with ml. of 5percent aqueous sodium bicarbonate solution and 30 ml. of saturatedaqueous sodium chloride solution. The ethyl acetate solvent is thenremoved by evaporation, under vacuum, affording a residue which isfurther purified by silica gel column chromatography, eluting with ethylacetatehexane mixture, yielding pure (dl)-2-(6-carbomethoxyhexyl)-4-hydroxy-l-oxo-cyclopent-2-ene.

240 Milligrams of 2-(6-carbomethoxy-hexyl)-4-hydroxy-l-oxo-cyclopent-2-ene is dissolved in 5 ml. of benzenecontaining 200 mg. of isopropenyl methyl ether at room temperature. Asmall drop of phosphorous oxychloride is added and the resulting mixtureis allowed to stand for two hours at room temperature. A drop oftriethylamine is then added and the resulting mixture is poured intowater and extracted with benzene. The benzene extract is sequentiallywashed with water and saturated aqueous sodium chloride, dried oversodium sulfate and evaporated, under vacuum, to remove excess solventyielding a residue of (d1)-2-(6-carbomethoxy-hexyl)-4-(2-methoxyprop-2-oxy)-loxo-cyclopent-2-ene.

Similarly, by following the same procedure but using the corresponding2-(carboalkoxy-alkyl)-cyclopent- 2-ene products of Preparation 5 asstarting materials, the following compounds are respectively prepared:

(dl)-2-(6-carboethoxy-hexyl)-4-(2'-methoxyprop-2-oxy)-l-oxo-cyclopent-2-ene;

(dl)-2-(6-carbohexoxy-hexyl)-4-(2'-methoxyprop-2'-oxy)-1-oxo-cyclopent-2-ene;

(dl)-2-(2-carbomethoxy-ethyl)-4-(2'-methoxyprop-2'-oxy)-l-oxo-cyclopent-2-ene;

(dl)-2-(2-carboethoxy-ethyl)-4-(2'-methoxyprop-2'-oxy)-l-oxo-cyclopent-2-ene;

(dl)-2-(2-carbohexyoxy-ethyl)-4-(2-methoxyprop-2-oxy)-l-oxo-cyclopent-Z-ene;

(dl )-2-( S-carbomethoxy-octyl )-4-( 2 -methoxypr0p-2'-oxy)-l-oxocyclopent-2-ene;

(dl)-2-(S-carboethoxy-octyl)-4-(2'-methoxyprop-2'-oxy)-l-oxo-cyclopent-Z-ene; and

(dl)-2-(8-carbohexoxy-octyl)-4-(2-methoxyprop-2-oxy)-l-oxo-cyclopent-2-ene.

Similarly, by following the same procedure as above but respectivelyreplacing isopropenyl methyl ether with isopropenyl ethyl ether, thecorresponding 4-(2-ethoxyprop-2-oxy) ether analogs of each of the aboveproducts is respectively prepared.

PREPARATION 7 This preparation illustrates methods of preparing 4-tetrahydropyranyl ethers 2-(carboalkoxy-alkyl)-l-oxocyclopent-Z-ene. Inthis preparation, 2.6 g. of 2-(6-carbomethoxy-hexyl)-4-hydroxy-l-oxo-cyclopent- 2-ene is dissolved in50ml. of benzene containing 2 ml. of dihydropyran at room temperature. Asmall drop of phosphorous oxychloride is added and the resulting mixtureis stirred for 1% hours. A drop of triethylamine is then added and theresulting mixture is poured into water and then extracted with benzene.The benzene extract is sequentially washed with water and saturatedaqueous sodium chloride, then dried over anhydrous sodium sulfate andevaporated, under vacuum, to remove excess solvent affording a residueof (dl)-2-(6- carbomethoxy-hexyl)-4-(tetrahydropyranyl-2-oxy)-loxo-cyclopent-Z-ene, which is further purified by chromatography onsilica gel eluting with graduated mixtures of ethyl acetate and hexane.

Similarly, by following the same procedure but using the corresponding2-(carboalkoxy-alkyl l -oxocyclopent-2-ene precursors as startingmaterials; the following compounds are respectively prepared:

(dl)-2-( 6-carboethoxy-hexyl)-4-(tetrahydropyranyl- 2 -oxy)- 1-oxo-cyc1opent-2-ene;

(dl)-2-(6-carbohexoxy-hexyl)-4-(tetrahydropyranyl-2'-oxy)-l-oxo-cyclopent-2-ene;

(dl)-2-(2-carbomethoxy-ethyl)-4- (tetrahydropyranyl-2 -oxy l-oxo-cylopent-2-ene;

(dl)-2-(2-carboethoxy-ethyl)-4-(tetrahydropyranyl-2-oxy)-l-oxo-cyclopent-2-ene;

(dl)-2-(2-carbohexoxy-ethyl)-4-(tetrahydropyranyl-2'-oxy)-l-oxo-cyclopent-2-ene;

(dl)-2-(8-carbomethoxy-octyl)-4-(tetrahydropyranyl-2-oxy)-l-oxo-cyclopent-Z-ene;

(dl)-2-(8-carboethoxy-octyl)-4-(tetrahydropyranyl-2-oxy)-l-oxo-cyclopent-2-ene; and

(dl )-2-( 8-carbohexoxy-octyl )-4-( tetrahydropyranyl- 2-oxy)-l-oxo-cycl0pent-2-ene.

PREPARATION 8 This preparation illustrates methods of preparing apancreatic lipase preparation which can be used to cleave ester groupsfrom prostanoic acid esters. In this preparation, 10 g. of crudepancreatic lipase (note; Biochem. Biophysics Acta., v. 23, page 2641957)) is suspended in 65 ml. of water at 0C. The suspension is stirredfor 1 hours at 0C and then centrifuged for 20 minutes at 10,000 xg. Thesupernatant liquid is separated and maintained at 0C for later use. Theprecipitate is again suspended in 65 ml. of water at 0C and centrifugedas before. The supernatant liquid is separated and combined with thepreviously obtained supernatant liquid and then added to 130 ml. ofsaturated aqueous ammonium sulfate solution at 0C, with stirring, andthen allowed to stand for 5 minutes. The resulting mixture is thencentrifuged at 10,000 xg. for 20 minutes. The supernatant liquid isdecanted and the precipitate is collected, then dissolved in sufficientwater to yield 125 ml. of solution. Fifteen milliliters of saturatedaqueous ammonium sulfate solution is then added to the water solutionyielding a suspension which is then centrifuged at 10,000 xg. for 20minutes. The supernatant liquid is collected and treated with ml. ofsaturated ammonium sulfate affording a second suspension, which isdivided into two equal portions. Each portion is again centrifuged for20 minutes at 10,000 xg., and in each instance the supernatant liquid isdis carded (decantation) and the precipitate collected. Each precipitateis stored at 40C, prior to use.

The pancreatic lipase ester cleaving preparation is then preparedimmediately prior to use by dissolving one of the above precipitates in25 ml. of an aqueous 0.1 mole sodium chloride and 0.05M calcium chloridesolution and then adjusting the pH to 7.2 by the careful addition (i.e.titration) of 0.1M aqueous sodium hydroxide solution.

EXAMPLE 1 This example illustrates methods, according to the invention,of preparing the reagents and compounds of the invention. In thisexample 6.7 ml. ofa 1.5M n-butyl lithium in hexane solution is admixedto a mixture containing 3.26 g. of (dl)-l-iodo-3-(2'-methoxyprop-2-oxy)-cis-1-octene in 8 ml. of hexane at 78C under an argon atmosphere.The resulting mixture is stirred and maintained at 78C, under argon, for30 minutes. During this time a second mixture containing 2.4 g. ofbis-trimethylphosphite copper" iodide in 60 ml. of diethyl ether isprepared and maintained under argon and cooled to 78C. At the end of the30 minute period, previously referred to, the first mixture is admixedto the second mixture and the temperature of the resulting mixture isbrought to 50C. The resulting mixture is periodically monitored by aGilman test [note; Gilman and Schulze, J. Am. Chem. Soc., v. 47, 2002(1925)], and maintained at -50C until a negative Gilman test is obtained(about 45 minutes). This mixture (a reagent of our invention) is thencooled to 78C and 1.1 g. of 2-(6-carbomethoxy-hexyl)-1-oxocyclopent-2enein 3 ml. of diethyl ether is added. The resulting mixture is stirred at78C for 2.5 hours yielding a(d1)-1SB-(Z'-methoxyprop-2'-oxy)-9-oxo-prostl3-cis-enoic acid methylester rich mixture. This mixture is poured into 100 ml. of 20 percentaqueous acetic acid and stirred at room temperature for 30 minutesyielding a two phase liquid-liquid mixture. The ether layer is separatedand extracted with 5 percent aqueous sodium bicarbonate solution untilthe aqueous solution is slightly basic. The ethyl ether is then removedby vacuum evaporation and the resulting residue is stirred at roomtemperature for 30 minutes with 100 ml. of percent aqueous ammonia andthen extracted with two 50 ml. portions of diethyl ether. The diethylether extracts are combined and evaporated under vacuum affording aresidue which is then chromatographed over 60 g. of silica gel elutingwith gradient mixtures of 15 percent (vol.) ethyl acetate-85 percenthexane to 50 percent (vol.) ethyl acetate-50 percent hexane, yielding(dl)-l5B-hydroxy-9-oxo-prost- 13-cis-enoic acid methyl ester.

This product is mixed with 30 ml. of5 percent methanolic potassiumhydroxide and then refluxed, under nitrogen. for 2 hours. The methanolis removed by vacuum evaporation and 100 ml. of water then added to theresidue. The water mixture is extracted with two 30 ml. portions ofdiethyl ether, and then made slightly acid by the addition ofconcentrated hydrochloric acid, then again extracted with three 30 ml.portions of fresh diethyl ether. The extracts are combined, then driedover anhydrous sodium sulfate, filtered. and evaporated to drynessyielding (dll-l5B-hydroxy-9-oxoprostl3-cis-enoic acid. which is thenfurther purified by recrystallization from ethyl acetatezcyclohexane.

Similarly, by following the same procedure, the following(dl)-l5-ether-l3-cis prostenoic acid esters are respectively prepared asproduct rich mixtures and the respective ether and ester groups thenstepwise cleaved and the respective (dl)-15-hydroxy-l3-cis prostenoicacid esters and (dl)-l5-hydroxy-l 3-cis prostenoic acids isolated:

(d1)-15/3-(2-methoxyprop-2'-oxy)-9-oxo-prost-l 3- cis-enoic acid ethylester;

(dl)-15B-(2-methoxyprop-2'-oxy)-9-oxo-prost-l3- cisenoic acid hexylester;

(dl)-6-desbutylene-l5/3-(2-methoxyprop-2'-oxy)-9- oxoprost-l3-cis-enoicacid methyl ester;

(d1 )-6-desbutylene- 1 5,8-( 2 -methoxyprop-2 '-oxy)-9-oxoprost-l3-cis-enoic acid ethyl ester;

(dl)-6-desbutylene-15[3-(2'-methoxyprop-2-oxy)-9- oxoprost-l 3-cis-enoicacid hexyl ester;

(dl)-6-homoethylene-15B-(2'-methoxyprop-2-oxy)- 9-oxoprost-l 3-cis-enoicacid methyl ester;

(dl)-6-homoethylene-l5,B-(2-methoxyprop-2'-oxy)- 9-oxoprost-l3-cis-enoicacid ethyl ester; and

(dl)-6-homoethylene-l5/3-(2-methoxyprop-2'-oxy)- 9-oxoprost-13-cis-enoicacid hexyl ester.

Similarly, by following the same procedure as above but respectivelyusing (d1)-1-iodo-3-(2'-butoxyprop-2- oxy)-cis- 1 -octene and(dl)-1-iodo-3-(1-pent-1"- oxycyclohexyl-l-oxy)-cis-1-octene in place of(dl)-1- iodo-3-(2methoxyprop-2-oxy)-cis-l-octene, the followingcompounds are respectively prepared as product rich mixtures and theether and ester groups cleaved and the resulting cleaved productsisolated:

(dl)- l 5,8-( 2'-butoxyprop-2'-oxy) 9-oxo-prostl 3- cisenoic acid methylester;

(dl)-l 5B-(2-butoxyprop-2'-oxy)-9-oxo-prost-13- cisenoic acid ethylester;

(dl )-1 5B-( 2 '-butoxyprop-2 -oxy)-9-oxo-prostl 3- cisenoic acid hexylester; I

(dl)-6-desbutylene-15,B-(2-butoxyprop-2'-oxy)-9- oxoprostl 3-cis-enoicacid methyl ester;

(dl)-6-desbutylene-15B-(2-butoxyprop-2'-oxy)-9- oxoprost-13-cis-enoicacid ethyl ester;

(dl)-6-desbutylene-15B-(2-butoxyprop-2'-oxy)-9- .oxoprost-l3-cis-enoicacid hexyl ester;

(dl )-6-homoethylenel 5,B-(2'-butoxyprop-2 -oxy )-9-oxoprost-lB-cis-enoic acid methyl ester;

(dl )-6-homoethylene- 1 5B-( 2 -butoxyprop-2 '-oxy )-9-oxoprost-l3-cis-enoic acid ethyl ester;

(dl)-6-homoethylene-1S,B-(2'-butoxyprop-2'-oxy)-9- oxoprost-l3-cis-enoicacid hexyl ester;

(dl)-l5,B-(1'-pent-l"-oxycyclohexyl-l'-oxy)-9-oxoprostl3-cis-enoic acidmethyl ester;

(dl)-l5B-(l-pent-1"-ox'ycyclohexyl-l-oxy)-9-oxoprost-l3-cis-enoic acidethyl ester;

(dl)-6-desbutylene-l5B-(l'-pent-1"-oxycyclohexyl-1'-oxy)-9-oxo-prost-l3-cis-enoic acid methyl ester;

(dl)-6-desbutylene- 1 5/3-( 1 -pent-l "-oxycyclohexyl-1'-oxy)-9-oxo-prost-l3-cis-enoic acid ethyl ester;

(dl)-6-desbutylene-15,B-(1-pent-l-oxycyclohexyl'-oxy)-9-oxo-prost-l3-cis-enoicacid hexyl ester;

(dl)-6homoethylene- 1 5B-( 1 -pent-1 oxycyclohexyl-l -oxy )-9-oxo-prost-l 3 -cis-enoic methyl ester;

(dl)-6-homoethylene-15B-( 1 '-pent-l oXycyclohexyl-l'-oxy)-9-oxo-prost-l 3-cis-enoic ethyl ester; and

(d1)-6-homoethylene-l5B-( l -pent-l oxycyclohexyl l '-oxy)-9-oxo-prostl3-cis-enoic hexyl ester.

acid

acid

acid

EXAMPLE 2 This example illustrates methods, according to the invention,of preparing the reagents and compounds of the invention. In thisexample 6.7 ml. ofa 1.5M n-butyl lithium in hexane solution is admixedto a mixture containing 3.26 g. of (R)-l-ido-3-(2'-methoxyprop-2'-oxy)-cis-l -octene in 8 ml. of hexane at 78C under an argon atmosphere.The resulting mixture is stirred and maintained at 78C, under argon, for30 minutes. During this time a second mixture containing 2.4 g. ofbis-trimethylphosphite copper" iodide in 60 ml. of diethyl ether isprepared and maintained under argon and cooled to 78C. At the end of the30 minute period, previously referred to, the first mixture is admixedto the second mixture and the temperature of the resulting mixture isbrought to -50C. The resulting mixture is periodically monitored by aGilman test [note; Gilman and Schulze, J. Am. Chem. Soc., v. 47, 2002(1925 )1, and maintained, at 50C until a negative Gilman test isobtained (about 45 minutes). This reagent mixture is then cooled to 78Cand 1.1 g. of 2-(6- carbomethoxy-hexyl)-loxo-cyclopent-2-ene in 3 ml. ofdiethyl ether is added. The resulting mixture is stirred at 78C for 2.5hours yielding at l5B-(2'- methoxyprop-Z oxy )-9-oxo-prostl 3-cis-enoicacid methyl ester rich mixture. This mixture is poured into I00 ml. ofpercent aqueous acetic acid and the resulting mixture stirred at roomtemperature for 30 minutes yielding a two phase liquid-liquid mixture.The ether layer is separated and extracted with 5 percent aqueous sodiumbicarbonate solution until the ether solution is slightly basic. Theethyl ether is then removed by vacuum evaporation and the resultingresidue is stirred at room temperature for 30 minutes with 100 ml. of15% aqueous ammonia and then extracted with two 50 ml. portions ofdiethyl ether. The diethyl ether extracts are combined and evaporatedunder vacuum affording a residue which is then chromatographed over 60g. of silica gel eluting with gradient mixtures of 15 percent (v0l.)ethyl acetate-85 percent hexane to 50 percent (vol.) ethyl acetate-50percent hexane, yielding l5fl-hydroxy-9-oxo-prost-l3cis-enoic acidmethyl ester.

The product is mixed with 30 ml. of5 percent methanolic potassiumhydroxide and then refluxed, under nitrogen. for two hours. The methanolis removed by vacuum evaporation and 100 ml. of water then added to theresidue. The water mixture is extracted with two 30 ml. portions ofdiethyl ether, and then made slightly acid by the addition ofconcentrated hydrochloric acid, then again extracted with three 30 ml.portions of fresh diethyl ether. The extracts are combined, then driedover anhydrous sodium sulfate, filtered, and evaporated to drynessyielding l5B-hydroxy-9-oxo-prost-l3- cis-enoic acid which is thenfurther purified by recrystallization from ethyl acetate-cyclohexane.

Similarly, by following the same procedure as above but in place of 2-(6-carbomethoxy-hexyl)-loxocyclopent-Z-ene respectively using thecorresponding products of Preparation 5 as starting materials, thefollowing compounds are respectively prepared as product rich mixturesand the respective ether and ester groups then stepwise cleaved and therespective 15B- hydroxy-lS-cis prostenoic acid esters and ISB- hydroxy-l3-cis prostenoic acids isolated:

l5B-( 2'-mcthoxyprop-2'-oxy )-9-oxo-prostl 3-cisenoic acid ethyl ester;

1 5B-( 2 methoxyprop-Z '-oxy )-9-oxo-prostl 3-cisenoic acid hexyl ester;

6-desbutylene- I 5,842-methoxyprop-Z-oxy)-9-oxoprost-lB-cis-enoic acidmethyl ester;

prost-l3-cis-enoic acid ethyl ester;

6-desbutylene- 1 5B-( 2-methoxyprop-2'-oxy)-9-oxoprost-l3-cis-enoic acidhexyl ester;

o-homoethylene-l5B-(2'-methoxyprop-2-oxy)-9- oxo-prost-l3-cis-enoic acidmethyl ester;

6-homoethylene-l5,B-(2'-methoxyprop-2-oxy)-9- oxo-prost-l 3-cis-enoicacid ethyl ester; and

6-homoethylene-15B-(2'-methoxyprop-2-oxy)-9- oxo-prost-l 3-cis-enoicacid hexyl ester.

Similarly, by following the same procedure as above but respectivelyusing (R)- l-iodo-3-(2-butoxyprop-2- oxy)-cis-l-octene and (R) l-iodo-3-( 1 '-pent-1 xyeys hea tis- 9teasimnbse f(R)-liodo-3-(2'-methoxyprop-2-oxy)-cis l-octene, the following compoundsare respectively prepared as product rich mixtures and the ether andester groups stepwise cleaved and the resulting cleaved productsisolated: l5,B-( 2-butoxyprop-2-oxy)-9-oxo-prost-l 3-cisenoic acidmethyl ester;

l5B-( 2'-butoxyprop-2 '-oxy)-9-oxo-prost-l 3-cisenoic acid hexyl ester;I

6-desbutylene-l5B-(2'-butoxyprop-2-oxy)-9-oxoprost-l3-cis-enoic acidmethyl ester;

6-desbutylene- 1 5B-( 2 -butoxyprop-2-oxy)-9-oxoprost-l 3-cis-enoic acidethyl ester; 6-desbutylene-15B-(2'-butoxyprop-2'-oxy)-9-oxo-prost-l3-cis-enoic acid hexyl ester;

6-homoethylenel 5,8-( 2'-butoxyprop-2 '-oxy)-9-oxoprost-l3-cis-enoicacid methyl ester;

-homoethylene- 1 5B-( 2 '-butoxyprop-2 -oxy)-9-oxoprost-l3-cis-enoicacid ethyl ester;

6-homoethylenel 5,l3-( 2'-butoxyprop-2 '-oxy)-9-oxo prost-l3-cis-en0icacid hexyl ester;

l5B-( l '-pent-l "-oxycyclohexyl-l '-oxy)-9-oxo-prostl3-cis-enoic acidhexyl ester;

15/3-( l -pentl "-oxycyclohexyl-l '-oxy)-9-oxo-prostl3-cis-en0ic acidhexyl ester;

6-desbutylene- 1 5B( 1 '-pent-l "-oxycyclohexyl-loxy)-9-0xo-prost-l3-cis-enoic acid methyl ester;

-desbutylene- 1 5B-( 1 '-pent-l "-oxycyclohexyl-loxy)-9-oxo-prost-l3-cis-enoic acid ethyl ester;

6-desbutylene-15B-( l -pent-l "-oxycyclohexyl-loxy)-9-oxo-prost-l3-cis-enoic acid hexyl ester;

6-homoethylene-l5B-( l '-pent-l "-oxycyclohexyl-loxy)-9-oxo-prost-l3-cis-enoic acid methyl ester;

6-homoethylene-l5B-( 1'-pent-l "-oxycyclohexyl-loxy-)-9-oxo-prost-l3-cis-enoic acid ethyl ester; and

-homoethylene- 1 5B-( 1 pent-l "-oxycyclohexyl-loxy)-9-oxo-prost-l3-cis-enoic acid hexyl ester.

EXAMPLE 3 This example illustrates methods, according to the inventionof preparing the reagents and compounds of the invention. In thisexample6.7 m]. ofa 1.5M n-butyl lithium in hexane solution is admixed to amixture containing 3.26 g. of (S)-liodo-3-(2'-methoxyprop-2'- oxy)-cis-loctene in 8 ml. of hexane at 78C under an argon atmosphere. Theresulting mixture is stirred and maintained at 78C, under argon, for 30minutes. During this time a second mixture containing 2.4 g. ofbis-trimethylphosphite copper iodide in 60 ml. of diethyl ether isprepared and maintained under argon and cooled to 78C. At the end of the30 minute period, previously referred to, the first mixture is admixedto the second mixture and the temperature of the resulting mixture isbrought to -50C. The resulting mixture is periodically monitored by aGilman test [note; Gilman and Schulze, J. Am. Chem. Soc., v. 47, 2002(1925) and maintained at 50C until a negative Gilman test is obtained(about 45 minutes). This reagent mixture is then cooled to -78C and 1.1g. of 2-(6- carbomethoxy-hexyl)-l-oxo-cyclo-pent-2-ene in 3 ml. ofdiethyl ether is added. The resulting mixture is stirred at 78C for 2.5hours yielding a retro-l SCI-(2'- methoxyprop-2 -oxy)-9oxo-prost-l3cis-enoic acid methyl ester rich mixture. This mixture is poured into100 ml. of 20 percent aqueous acetic acid and the resulting mixturestirred at room temperature for 30 minutes yielding a two phaseliquid-liquid mixture. The ether layer is separated and extracted with 5percent aqueous sodium bicarbonate solution until the ether solution isslightly basic. The ethyl ether is then removed by vacuum evaporationand the resulting residue is stirred at room temperature for 30 minuteswith 100 ml. of i5 percent aqueous ammonia and then extracted with two50 ml. portions of diethyl ether. The diethyl ether extracts arecombined and evaporated under vacuum affording a residue which is thenchromatographed over 60 g. of silica gel eluting with gradient mixturesof 15 percent (vol.) ethyl acetate-85 percent hexane to 50 percent(vol.) ethyl acetate-50% hexane, yielding retro-l5a-hydroxy-9-oxo-prostl 3- cis-enoic acid methyl ester.

This product is mixed with 30 ml. of 5 percent methanolic potassiumhydroxide and then refluxed, under nitrogen, for two hours. The methanolis removed by vacuum evaporation and I ml. of water then added to theresidue. The water mixture is extracted with two 30 m1. portions ofdiethyl ether, and then made slightly acid by the addition ofconcentrated hydrochloric acid, then again extracted with three 30 ml.portions of fresh diethyl ether. The extracts are combined, then driedover anhydrous soidum sulfate, filtered, and evaporated to drynessyielding retro-la-hydroxy-9 oxoprostl3-cis-enoic acid which is thenfurther purified by recrystallization from ethyl acetate-cyclohexane.

Similarly, by following the same prodecure as above but in place of2-(6carbomethoxy-hexyl)-l-oxocyclopent-2'ene respectively using thecorresponding oxy)-cis-l-octene and (S)-liodo-3-( l '-pent-loxycyclohexyl-l -oxy)- cis-l-octene in place of(S)-liodo-3-(2-methoxyprop-2-oxy)-cisl-octene, the following compoundsare respectively prepared as product rich mixtures and the ether andester groups then stepwise cleaved and the resulting cleaved productsprost-l3-cis-enoic acid methyl ester;

retro-150:41'-pent-l"-oxycyclohexyl-l-oxy)-9-oxoprost-l3-cisenoic acidethyl ester;

retro-15a-( l -pent-l "-oxycyclohexyl-l '-0xy)-9-oxoprost-l3-cis-enoicacid hexyl ester;

retro--desbutylene- 1 5a-( 1 -pent-l"-oxycyclohexyll'-oxy)-9-oxo-prost-l3-cis-enoic acid methyl ester;

retro-o-desbutylene-l 5a-( 1 '-pent-l"oxycyclohexyll-oxy)-9-oxo-prost-l3-cis-enoic acid ethyl ester;

retro-b-desbutylene- 1 501-( l '-pent-l"-oxycyclohexyll'-oxy)-9-oxo-prost-l3-cis-enoic acid hexyl ester;

retro--homoethylene- 1 5a-( 1 '-pent-l oxycyclohexyl-l'-oxy)-9-oxo-prostl 3-cis-enoic acid 0 methyl ester;

retro-6-homoethylene-15oz-(1-pent-l"- oxycyclohexyl-l'-oxy)-9-oxo-prostl S-cis-enoic acid products of Preparation 5 asstarting materials, the following compounds are respectively prepared asproduct rich mixtures and the respective ether and ester groups thenstepwise cleaved and the respective retrol5oz-hydroxy-l3-cis prostenoicacid esters and retrolSa-hydroxy-lS-cis prostenoic acids isolated:

retro- 1 5a-( 2-methoxyprop-2'-oxy)-9-oxo-prost-l 3- cis-enoic acidethyl ester;

retro-lSat-(2'-methoxyprop-2-oxy)-9-oxo-prost-l3- cis-enoic acid hexylester;

retro--desbutylenel 5a (2-methoxyprop-2-oxy)- 9-oxo-prost-l3-cis-enoicacid methyl ester;

retro--desb-utylene-l5a-(2'-methoxyprop-2'-oxy)- 9-oxo-prostl3-cis-enoic acid ethyl ester;

rclro-(i-desbutylcnel 5a-( 2-methoxyprop-2-oxy)-Q-oxo-prost-lS-cis-enoic acid hexyl ester;

retro (i-homoethylene-l5a-(2'-methoxyprop-2'-oxy)9-oxo-prost-l3-cis-enoic acid methyl ester;

rctro-o-homoethylenel 5a-(2-methoxyprop-2- oxyi-Q-oxoprost-l3-cis-enoicacid ethyl ester; and

retro-o-homoethylene-l5a(2'-methoxyprop-2'-methoxypropi'-oxy)-9-oxo-prost-l 3-cis-enoic hexyl ester.

Similarly, by following the same procedure as above but respectivelyusing (S)-1-iodo-3-(2'-butoxyprop-2'- acid -homoethylene- 1 5a-( 1-pent-l acid EXAMPLE 4 This example illustrates methods, according tothe invention, of preparing the reagents and compounds of the invention.In this example 5 ml. of a 1.5M n-butyl lithium in hexane solution isadmixed to a mixture containing 2.5 g. of (dl)1-iodo-3-(2'-methoxyprop-2- oxy)-cis-l -octene in 5 ml. of hexane at 78C underan argon atomosphere. The resulting mixture is stirred and maintained at78C, under argon, for 30 minutes. During this time a second mixturecontaining 1.8 g. of bis-trimethylphosphite copper" iodide in 50 ml. ofdiethyl ether is prepared and maintained under argon and cooled to 78C.At the end of the 30 minute period, previously referred to, the firstsolution is admixed to the second solution and the temperature of theresulting mixture is brought to 50C. The resulting mixture isperiodically monitored by a Gilman test [note; Gilman and Schulze, J.Am. Chem. Soc., v. 47, 2002 (1925)], and stirred and maintained at -50Cuntil a negative Gilman test is obtained (about 20 minutes). Thisreagent mixture is then cooled to 78C and 0.298 g. of(dl)-2-(6-carbomethoxy-hexyl)-4-(2'-rnethoxyprop-2-oxy)-l-oxo-cyclopent-2-ene in 3 ml. of diethyl ether isadded. The resulting mixture is stirred at 78C for two hours yielding a(dl)-l la,l5B-bis(2- methoxyp top-2 '-oxy )-9-oxo-prost-l 3-cis-enoicacid methyl ester rich mixture. This mixture is poured into 100 ml. of20 percent aqueous acetic acid and the resulting mixture stirred at roomtemperature for 30 minutes yielding a two phase liquid-liquid mixture.The ether layer is separated and evaporated under vacuum to remove theether solvent. The residue is chromatographed on l g. of silica gel(which is previously deactivated with l g. of formic acid) using agradient mixture of from one to 1 /2 to 4:1, by vol., ethyl acetate:-hexane mixtures, yielding (dl)-l la,lB-dihydroxy-9-oxo-prost-l3-cis-enoic acid methyl ester.

Similarly, by following the same procedure but respectively using(dl)-2-(2carbomethoxy-ethyl)-4-(2-methoxyprop-2'-oxy)-l-oxo-cyclopent-2-ene and (dl)-2-(8-carbomethoxy-octyl)-4-(2'-methoxyprop-2- oxy)l-oxo-cyclopent-2-enein place of (dl)-2-(6- carbomethoxy-hexyl )-4-( 2 methoxyprop-2 -oxy)-loxo-cyclopent-Z-ene, the following enantiomeric mixtures arerespectively prepared as product rich mixtures:

(dl)-l la,l5/3-bis(2'-methoxyprop-2-oxy)-6-desbutylene-9-oxo-prost-l3-cis-enoicacid methyl ester; and

(dl)-l la,l5B-bis(2'-methoxyprop-2'-oxy)-6-homoethylene9-oxo-prost-l3-cis-enoic acid methyl ester.

Similarly, by following the same procedure using the remaining 1 l-etherand ester products of Preparation 6 as starting materials, thecorresponding enantiomeric mixtures are respectively prepared as productrich mixtures.

Similarly, by following the same procedure using the remaining(dl)-liodo-3-ether-cis-l-octene products of Preparation 2 as startingmaterials, the corresponding (dl)-l 5-ether analogs of the aboveproducts are respectively prepared as product rich mixtures.

The C11 and C-l5 ether groups are then cleaved from each of the aboveproduct rich mixtures via treatment with percent aqueous acetic acid andthe respective (dl)-lla,l5B-dihydroxy-l3-cis prostenoic acid esterproducts isolated by chromatography, as described above.

EXAMPLE 5 This example illustrates methods, accordingto the invention,of preparing the reagents and compounds of the invention. In thisexample 5 ml. of a 1.5M n-butyl lithium in hexane solution is admixed toa mixture containing 2.5 g. of (R)- l-iodo-3-(2'-methoxyprop-2'-oxy)-cisl octene in 5 ml. of hexane at 78C under an argon atmosphere.The resulting mixture is stirred and maintained at 78C, under argon, for30 minutes. During this time a second mixture containing 1.8 g. ofbis-trimethylphosphite copper" iodide in 50 ml. of diethyl ether isprepared and maintained under argon and cooled to 78C. At the end of the30 minute period, previously referred to, the first solution is admixedto the second solution and the temperature of the resulting mixture isbrought to 50 C. The resulting mixture is periodically monitored by aGilman test [note; Gilman and Schulze, J. Am. Chem. Soc., v. 47, 2002(1925)], and stirred and maintained at -50C until a negative Gilman testis obtained (about 20 minutes). This reagent mixture is then cooled to 78C and 0.298 g. of (dl)-2-( fi-carbomethoxy-hexyl)-4-(2'-methoxvprop-2'-oxv)-loxo-cyclopent-Z-ene in 3 ml.

of diethyl ether is added. The resulting mixture is strired at 78C for 2hours yielding a l la,l5[3-bis(2-methoxyprop-2'-oxy)-9-oxo-prost-l3-cis-enoic acid methyl ester richmixture. This mixture is poured into ml. of 20 percent aqueous aceticacid and the resulting mixture stirred at room temperature for 30minutes yielding a two phase liquid-liquid mixture. The ether layer isseparated and evaporated under vacuum to remove the ether solvent. Theresidue is chromatographed on 100 g. of silica gel (which is previouslydeactivated with l g. of formic acid) using a gradient mixture of from 1to 1 /2 to 4:1, by vol., ethyl acetatezhexane mixtures, yielding ll01,1SB-dihydroxy-9-oxo-prostl3-cis-enoic acid methyl ester.

Similarly, by following the same procedure but respectively using(dl)-2-(2-carbomethoxy-ethyl)-4-(2'- methoxypro p-2 -oxy loxo-cyclopent-Z-ene and (dl)-2-( S-carbomethoxy-octyl 4-( 2-methoxyprop-2 -oxy l oxo-cyclopent-2-ene in place of (d1)-2-(6-carbomethoxy-hexyl )-4-( 2methoxyprop-2'-oxy)-loxo-cyclopent-2-ene, the following compounds arerespectively prepared as product rich mixtures:

l 1a,]5l3-bis(2methoxyprop-Z-oxy)-6-desbutylene-9-oxo-prost-l3-cis-enoic acid methyl ester; and

l la,l5/3-bis(2'-methoxyprop-2'-oxy)-6-homoethylene-9-oxo-prost-l3-cis-enoic acid methyl ester.

Similarly, by following the same procedure using the remaining ll-etherand ester products of Preparation 6 as starting materials, thecorresponding compounds are respectively prepared as product richmixtures.

Similarly, by following the same procedure using the remaining(R)-l-iodo-3-ether-cis-loctene products of Preparation 2 as startingmaterials, the corresponding l5-ether analogs of the above products areprepared as product rich mixtures.

The C-ll and C-15 ether groups are then cleaved from each of the aboveproduct rich mixtures via treatment with 20 percent aqueous acetic acidand the respective lla,l5B-dihydroxy-l3-cis prostenoic acid esterenantiomers isolated by chromatography, as described above.

EXAMPLE 6 This example illustrates methods, according to the invention,of preparing the reagents and compounds of the invention. In thisexample 5 ml. of a 1.5M n-butyl lithium in hexane solution is admixed toa mixture containing 2.5 g. of (S)-l-iodo-3-(2-methoxyprop-2- oxy)-cis-loctene in 5 ml. of hexane at 78C under an argon atmosphere. Theresulting mixture is stirred and maintained at 78C, under argon, for 30minutes. During this time a second mixture containing 1.8 g. ofbistrimethylphosphite copper" iodide in 50 ml. of diethyl ether isprepared and maintained under argon and cooled to 78C. At the end of the30 minute period, previously referred to, the first solution is admixedto the second solution and the temperature of the resulting mixture isbrought to 50C. The resulting mixture .g. of(dl)-2-(6-carbomethoxy-hexylJ-4-(2-methoxyprop-2-oxy)-loxocyclopent-Z-enein 3 ml. of diethyl ether is added. The resulting mixture is stirred at78C for 2 hours vieldint'. a retro-llB.l5a-bis(2-methoxyprop-Z-oxy)-9-oxo-prost-l 3-cis-enoic acid methyl ester richmixture. This mixture is poured into 100 ml. of 20 percent aqueousacetic acid and the resulting mixture stirred at room temperature for 30minutes yielding a two phase liquid-liquid misture. The ether layer isseparated and evaporated under vacuum to remove the ether solvent. Theresidue is chromatographed on 100 g. of silica gel (which is previouslydeactivated with l g. of formic acid) using a gradient mixture of from 1to 1 /2 to 4:1, by vol., ethyl acetate:hexane mixtures, yielding retrollB,l Sa-dihydroxy-9-oxo-prostl 3-cis-en0ic acid methyl ester. 7

Similarly, by following the same procedure but respectively using(dl)-2-(2-carbomethoxy-ethyl)-4-(2'-methoxyprop-2'-oxy)-l-oxo-cyclopent-2-ene and (dl)-2-(8-carbomethoxyoctyl)-4-(2'-methoxyprop-2'-oxy)- l-oxo-cyclopent-Z-enein place of (dl)-2-(6- carbomethoxy-hexyl)-4-(2"-methoxyprop-2-oxy)-l-oxo-cyclopent-2-ene, the following compounds are respectivelyprepared as product rich mixtures:

retro-llB,15a-bis(2-methoxyprop-2'-oxy)-6-desbutylene-9-oxo'prost-l3-cis-enoicacid methyl ester; and

retro-l 1B, 1 5a-bis(2-methoxyprop-2'-oxy)-6-homoethylene-9-oxo-prost-l3-cis-enoic acid methyl ester.

Similarly, by following the same procedure using the remaining esterproducts of Preparation 6, as starting material, the correspondingcompounds are respectively prepared as product rich mixtures.

Similarly, by following the same procedure using the remaining(S)-l-iodo-3-ether-cis-l-octene products of Preparation 2 as startingmaterials, the corresponding l5-ether analogs of the above products areprepared as product rich mixtures.

The C-ll and C-l5 ether groups are then cleaved from each of the aboveproduct rich mixtures via treatment with percent aqueous acetic acid andthe respective retro-11,8,l5a-dihydroxy-l3-cis prostenoic acid esterenantiomers isolated by chromatography, as described above.

EXAMPLE 7 This example illustrates methods, according to the invention,of preparing the reagents and compounds of the invention. In thisexample 5 ml. of a 1M n-butyl lithium in hexane solution is admixed to amixture containinng 2.5 g. of(dl)-liodo-3-(2-methoxyprop-2-oxy)-cis-1-octene in 5 ml. of hexane at78C under an argon atmosphere. The resulting mixture is stirred andmaintained at 78C, under argon, for minutes. During this time a secondmixture containing 1.8 g. of bis-trimethylphosphite copper" iodide in 50ml. of diethyl ether is prepared and maintained under argon and cooledto -78C. At the end of the 30 minute period, previously referred to, thefirst solution is admixed to the second solution and the temperature ofthe resulting mixture is brought to 50C. The resulting mixture isperiodically monitored by a Gilman test [note; Gilman and Schulze, J.Am. Chem. Soc., v. 47, 2002 1925)], and stirred and maintained at -5 0Cuntil a negative Gilman test is obtained (about 20 minutes). The reagentmixture is then cooled to 78C and 0.310 g. of (dl)-2-(6-carbomethoxy-hexyl)-4-(tetrahydropyranyl-Z'-oxy)- l oxo-cyclopent-Z-enein 3 ml. of diethyl ether is added. The resulting mixture is stirred at78C for two hours yielding a (dl)-l5,6-(2-methoxyprop-2'-oxy)- 1 la-(tetrahydropyranyl-Z'-oxy)-prostl 3-cis-en0ic acid methyl ester richmixture. This mixture is poured into ml. of 20 percent aqueous aceticacid and the resulting mixture stirred at room temperature for 30minutes yielding a two phase liquid-liquid mixture. The ether layer isseparated and evaporated under vacuum to remove the ether solvent. Theresidue is chromatographed on 100 g. of silica gel (which is previouslydeactivated with l g. of formic acid) using a gradient mixture of from 1to l A to 4:1, by vol., of ethyl acetate:- hexane mixtures, yielding(dl)-l5B-hydroxy-9-oxol lg ttetrahydropyranyli'-0xy) prost-l 3-cis-enoic,atligl methyl ester.

Similarly, by following the same procedure but respectively using (dl)2-(Z-carbomethyxy-ethyl)-4-(tetrahydropyranyl-2'-oxy)-loxo-cyclopent-2-ene and(dl)-2-(8-carbomethoxy-octyl)-4-(tetrahydropyranyl-2'-oxy)-l-oxo-cyclopent-2-ene in place of (dl)-2-(6- carbomethoxy-hexyl)-4-( tetrahydropyranyl-2 oxy l oxo-cyclopent-Z-ene. the followingenantiomeric mixtures are respectively prepared as product richmixtures:

(dl)-l5/3-(2'-methoxyprop-2'-oxy)-6-desbutylene-9- oxo-l1a-(tetrahydropyranyl-2-oxy)-13-cis-enoic acid methyl ester; and

(dl)-l5B-(2-methoxyprop-2oxy)-6-homoethylene- 11a-(tetrahydropyranyl-Z-oxy)-9-oxo-prostl 3-cisenoic acid methyl ester.g V

Similarly, by following the same procedure using the remaining esterproducts of Preparation 7, as starting materials, the correspondingenantiomeric mixtures are respectively prepared as product richmixtures.

Similarly, by following the same procedure using the remaining(dl)-1-iod0-3-ether-cis-l-octene products of Preparation 2 as startingmaterials, the corresponding l5-ether analogs of the products preparedabove as product rich mixtures are also prepared as product richmixtures.

The C-lS position ether group is then cleaved from each of the aboveproduct rich mixtures via treatment with 20 percent aqueous acetic acidand the respective (dl)-l5,B-hydroxy-'l la-ether-9-oxo-prost-l3-cis-enoic acid esters isolated by chromatography, as described above.

EX AM PLE 8 This example illustrates methods, according to theinvention, of preparing the reagents and compounds of the invention. Inthis example 5 ml. of a 1M n-butyl lithium in hexane solution is admixedto a mixture containing 2.5 g. of (R)-l-iodo-3-(2-methoxyprop-2-oxy)-cis-l-octene in 5 ml. of hex ane at 7 8C under anargon atmosphere. The resulting mixture is stirred and maintained at78C, under argon, for 30 minutes. During this time a second mixturecontaining 1.8 g. of bistrimethylphosphite copper" iodide in 50 ml. ofdiethyl ether is prepared and maintained under argon and cooled to 78C.At the end of the 30 minute period, previously referred to, the firstsolution is admixed to the second solution and the temperature of theresulting mixture is brought to 50C. The resulting mixture isperiodically monitored by a Gilman test [note; Gilman and Schulze, .I.Am. Chem. Soc., v. 47, 2002 l925)l. and stirred and maintained at 50Cuntil a negative Gilman test is obtained (about 20 minutes). Thisreagent mixture is then cooled to 78C and 0.310 g. of (d|)-2-(6-

1. A PROCESS FOR PREPARING 13-CIS PROSTAGLANDIN DERIVATIVES WHICHCOMPRISES TREATING A COMPOUND HAVING THE FORMULA:
 2. A process forpreparing 13-cis prostaglandin derivatives which comprises treating acompound having the formula:
 3. The process of claim 2 in which in (a)said iodooctenol ether is selected from the group consisting of:(dl)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(S)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(R)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(dl)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene;(S)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene;(R)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene; and thetemperature is in the range of from about -80* to 0* C, and in (b) thetrialkyl phosphite is trimethyl phosphite.
 4. A process for preparing13-cis prostaglandin derivatives which comprises treating a compoundhaving the formula:
 5. The process of claim 4 in which in (a) saidiodooctenol ether is selected from the group consisting of:(dl)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(S)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(R)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(dl)-1-iodo-3-(tetrahydropyraNyl-2''-oxy)-cis-1-octene;(S)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene;(R)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene; and thetemperature is in the range of from about -80* to 0* C and in (b) thetrialkyl phosphine is tri(n-butyl)phosphine.
 6. A process for preparing13-cis prostaglandin derivatives which comprises treating a compoundhaving the formula:
 7. The process of claim 6 in which in (a) saidiodooctenol ether is selected from the group consisting of:(dl)-1-iodo-3-(2''-methoxyprop-2'' -oxy)-cis-1-octene;(S)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(R)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(dl)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene;(S)-1iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene;(R)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene; and thetemperature is in the range of from about -80* to 0*c.
 8. A process forpreparing 13-cis prostaglandin derivatives which comprises treating acompound having the formula:
 9. The process of claim 8 in which in (a)said iodooctenol ether is selected from the group consisting of:(dl)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(S)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(R)-1-iodo-3-(2''-methoxyprop-2''-oxy)-cis-1-octene;(dl)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene;(S)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene;(R)-1-iodo-3-(tetrahydropyranyl-2''-oxy)-cis-1-octene; and thetemperature is in the range of from about -80* to 0* C.
 10. A processfor preparing 13-cis prostaglandin derivatives which comprises treatinga compound having the formula:
 11. The process of claim 10 in which thefreshly prepared composition is a mixture of compounds of the opticallyactive (S) isomers.
 12. The process of claim 10 in which the freshlyprepared composition is a mixture of compounds of the optically active(R) isomers.
 13. The process of claim 10 in which OR is2''-methoxyprop-2''-oxy.
 14. The process of claim 10 in which saidcomplexing reagent is tri(n-butylphosphine).